Amyotrophic lateral sclerosis (ALS) is a multifaceted disorder that almost certainly arises (most commonly) from a complex interplay between genetic risk, environmental exposure and stochastic events. Increasingly, it is also recognized that the clinical course of disease is determined independently of the risk of disease. And while some genetic determinants of disease progression have been identified, almost nothing is known about the environmental factors that impact the course of disease. This study will examine the influence of non-genetic factors and gene-environmental interactions on ALS disease progression, and will also explore the influence of gene-environmental interactions on the odds of developing ALS. These goals will be accomplished by leveraging the significant opportunity afforded to us by the recent establishment of the Clinical Research in ALS and related disorders for Therapeutic Development (CReATe) Consortium as part of the NIH-funded Rare Diseases Clinical Research Network (RDCRN). We will add detailed environmental exposure data to the prospectively and systematically collected deep phenotypic data and whole genome sequencing data that CReATe will collect on 500 patients with ALS, and will employ innovative approaches such as case-only analyses and Mendelian Randomization to address our specific aims. Importantly, this work will also elucidate an approach for future meaningful use of the `case-only' environmental exposure data being collected through the online portal of the National ALS Registry. This work, therefore, advances of the over-arching aims of the National ALS Registry and looks to the future as the scope of the National ALS Registry potentially broadens to encompass longitudinal data collection as well as banking of biological samples (including DNA).